The current novel coronavirus disease (COVID-19) has spread globally within a matter of months. The virus establishes a success in balancing its deadliness and contagiousness, and causes substantial differences in susceptibility and disease progression in people of different ages, genders and pre-existing comorbidities. These host factors are subjected to epigenetic regulation; therefore, relevant analyses on some key genes underlying COVID-19 pathogenesis were performed to longitudinally decipher their epigenetic correlation to COVID-19 susceptibility. The genes of host angiotensin-converting enzyme 2 (ACE2, as the major virus receptor) and interleukin (IL)-6 (a key immuno-pathological factor triggering cytokine storm) were shown to evince active epigenetic evolution via histone modification and cis/trans-factors interaction across different vertebrate species. Extensive analyses revealed that ACE2 ad IL-6 genes are among a subset of non-canonical interferon-stimulated genes (non-ISGs), which have been designated for their unconventional responses to interferons (IFNs) and inflammatory stimuli through an epigenetic cascade. Furthermore, significantly higher positive histone modification markers and position weight matrix (PWM) scores of key cis-elements corresponding to inflammatory and IFN signaling, were discovered in both ACE2 and IL6 gene promoters across representative COVID-19-susceptible species compared to unsusceptible ones. The findings characterize ACE2 and IL-6 genes as non-ISGs that respond differently to inflammatory and IFN signaling from the canonical ISGs. The epigenetic properties ACE2 and IL-6 genes may serve as biomarkers to longitudinally predict COVID-19 susceptibility in vertebrates and partially explain COVID-19 inequality in people of different subgroups.

中文翻译：

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ACE2和IL-6基因的表观遗传进化：非规范干扰素刺激的基因与脊椎动物的COVID-19易感性相关

当前的新型冠状病毒病（COVID-19）已在短短几个月内在全球蔓延。该病毒在平衡其截止日期和传染性方面取得了成功，并在不同年龄，性别和既往合并症的人群中造成了易感性和疾病进展方面的重大差异。这些宿主因子受到表观遗传调控。因此，对COVID-19发病机理的一些关键基因进行了相关分析，以纵向解读它们与COVID-19易感性的表观遗传相关性。宿主血管紧张素转化酶2（ACE2，作为主要病毒受体）和白介素（IL）-6（触发细胞因子风暴的关键免疫病理因子）的基因显示出通过组蛋白修饰和顺式/顺式活跃的表观遗传进化不同脊椎动物物种间的反式相互作用。大量分析表明，ACE2 ad IL-6基因属于非规范干扰素刺激基因（non-ISG）的子集，这些基因因其通过表观遗传级联对干扰素（IFN）和炎症刺激的非常规反应而被指定。此外，关键顺式的阳性组蛋白修饰标记和位置权重矩阵（PWM）得分明显更高与代表性的COVID-19易感物种相比，在代表性的COVID-19易感物种中ACE2和IL6基因启动子中均发现了与炎症和IFN信号传导相对应的E-元素。该发现将ACE2和IL-6基因表征为非ISG，它们对规范ISG的炎症和IFN信号传导反应不同。ACE2和IL-6基因的表观遗传特性可作为生物标志物，以纵向预测脊椎动物中COVID-19的敏感性，并部分解释不同亚组人群的COVID-19不平等。